Objective
The objective of the study was to compare 3-dimensional power Doppler (3DPD) of the uteroplacental circulation space (UPCS) in the first trimester between women who develop preeclampsia (PEC) and those who do not and to assess the 3DPD method as a screening tool for PEC.
Study Design
This was a prospective observational study of singleton pregnancies at 10 weeks 4 days to 13 weeks 6 days. The 3DPD indices, vascularization index (VI), flow index (FI), and vascularization flow index (VFI), were determined on a UPSC sphere biopsy with the virtual organ computer-aided analysis (VOCAL) program.
Results
Of 277 women enrolled, 24 developed PEC. The 3DPD indices were lower in women who developed PEC. The area under the receiver-operating characteristics curve for the prediction of PEC was 78.9%, 77.6%, and 79.6% for VI, FI, and VFI, respectively.
Conclusion
Patients who develop PEC have lower 3DPD indices of their UPCS during the first trimester. Our findings suggest that this ultrasonographic tool has the potential to predict the development of PEC.
Normal development of the intervillous space during the first trimester is crucial to proper fetal-maternal interaction. Pivotal to this is the trophoblast-mediated modification of the small-caliber spiral arteries into wide-caliber uteroplacental vessels that deliver blood to the intervillous space and ultimately to the placenta at low pressure. Inadequate modification of the spiral arteries resulting in decreased blood flow to the placenta has been implicated in the pathophysiology of preeclampsia.
Advances in both ultrasound and the knowledge of the pathophysiology of preeclampsia have revived attempts at finding a screening method for the disorder with the focus shifted to identifying a screening program for the first trimester. Current imaging methods, including first trimester uterine artery pulsatility index (UAPI) or resistive index and placental volume, have low detection rates for preeclampsia and are improved only if detection of severe cases requiring early delivery are the focus. This may be because these methods represent an indirect assessment of the abnormal placentation process.
The addition of maternal serum markers such as placental protein 13 and pregnancy-associated plasma protein A (PAPP-A), which are likely to better reflect the placentation process, are predicted to significantly improve screening sensitivity.
The introduction of 3-dimensional (3D) ultrasound technologies, with the option of imaging vascular volumes, has created an excellent opportunity to study early changes in the uteroplacental circulation space (UPCS), which includes the maternal spiral arteries and the intervillous space.
This technology may therefore allow a more direct evaluation of the abnormal placentation process that occurs with preeclampsia and particular findings that may herald the development of preeclampsia. In this study, we sought to: (1) compare first-trimester 3D power Doppler (3DPD) indices of the UPCS in patients who developed preeclampsia and those who did not; and (2) evaluate 3DPD of the UPCS as a potential first-trimester screening method for preeclampsia.
Materials and Methods
We conducted a prospective observational study in singleton pregnancies. All patients, 18 years old and older, who were attending our center for routine screening for chromosomal abnormalities by measurement of fetal nuchal translucency (NT) thickness and maternal serum-free beta-human chorionic gonadotropin and PAPP-A at a gestation of 10 weeks 4 days to 13 weeks 6 days were invited to participate.
The study was approved by our institutional review board, and written informed consent was obtained from all participants. Patients with multiple gestations or anomalous fetuses were excluded. Patients’ demographic data were extracted from their prenatal electronic records. This included maternal age; parity; ethnicity; medical history (including chronic hypertension, diabetes mellitus, antiphospholipid syndrome, thrombophilia, and sickle cell disease); obstetrical history (including previous pregnancy with preeclampsia); and medications (including antihypertensive medications). Maternal weight and height were measured and the body mass index (BMI) was calculated.
A single researcher (P.D.) performed all the ultrasound scans and the 3DPD analysis using Voluson 730 Expert (GE, Milwaukee, WI). Following transabdominal measurements of the crown-rump length (CRL) and NT, the uteroplacental interface was identified, and power Doppler was applied avoiding the fetus. The power Doppler settings were preadjusted on all machines to allow capture of weak signals that are common in the intervillous space, in addition to spiral arteries, and settings were maintained constant for all cases: image quality at high 1, color gain at 1.6, pulse repetition frequency at 0.6 kHz, and wall motion filter at 50 Hz. All other Doppler and sonographic settings were at the manufacturer default settings.
The 3D volume box was placed to contain, in addition to the uteroplacental interface, the placenta and the myometrium. After asking the patient to hold her breath and remain still for 10 seconds, a sweeping angle of 50° was used while the 3D volume was acquired. In the multiplanar view, the A plane was adjusted using the Z-axis knob to bring the uteroplacental interface axis to a transverse position in the center of the screen with the myometrium above and placenta below that axis.
Optimal zooming (×1.5-1.8) was achieved and a spherical volume biopsy with a diameter of 2 cm was sampled. One pole was placed at the upper end of the uteroplacental circulation and the other pole at the placenta ( Figure 1 ). The spherical volume was then analyzed with the virtual organ computer-aided analysis program (VOCAL; GE) to determine the vascularization index (VI; the ratio between color voxels and total voxels expressed in percentages), flow index (FI; the sum of the color voxels’ signal intensity divided by the number of color voxels, quantified between 0 and 100), and vascularization flow index (VFI; the sum of color voxels’ signal intensity divided by the total tissue voxels, quantified between 0 and 100).
The uterine arteries were then identified and the pulsatility index was measured bilaterally. Because many placentas at this stage of pregnancy may appear to have both anterior and posterior implantation sites, the placental location was recorded according to sphere location. For example, if a placenta appeared to extend from the anterior to the posterior uterine wall and the volume was rendered from the posterior part, the placenta was recorded as posterior. Maternal serum was sent for PAPP-A as part of the aneuploidy screening program.
Patients were followed up to the end of their pregnancies and outcome data were compiled. The primary outcome data were whether patients developed preeclampsia, defined by criteria outlined by the American College of Obstetrics and Gynecology. Briefly, patients had to have systolic blood pressures of 140 mm Hg or diastolic blood pressures of 90 mm Hg or higher occurring after 20 weeks of gestation with proteinuria, defined as urinary excretion of 0.3 g protein or higher in a 24-hour urine specimen. The results of the 3D Doppler studies were not shared with the patients or their providers and did not affect the management of their pregnancies.
Statistical analysis
SAS version 9.1.3 (SAS Institute, Cary, NC) was used for statistical analysis. Maternal demographic characteristics for both the preeclampsia and control group were compared using the Student t test, Wilcoxon test, and Fisher’s exact tests. The distribution of VI, FI, and VFI was analyzed with the Kolmogorov-Smirnov test. The indices were plotted against CRL and correlation was evaluated by the Pearson’s correlation test.
The 3DPD indices were compared between patients who developed preeclampsia and unaffected patients. Multivariate logistic regression analysis was used to determine which 3DPD indices significantly predicted preeclampsia, adjusting for the maternal and gestational characteristics. Screening accuracy for each index was assessed through receiver-operating characteristics (ROC) curves. Overall accuracy was estimated with the area under the ROC curve and associated 95% confidence interval (CI). P < .05 was considered statistically significant.
Results
Two hundred seventy-seven patients were enrolled. Eight patients (2.9%) had second-trimester spontaneous abortions, 1 patient (0.4%) had a voluntary termination, and 10 patients (3.6%) were lost to follow-up. Of the remaining 258 patients, 24 (9.3%) developed preeclampsia and 234 (90.7%) patients did not. Among those with preeclampsia, 12 (50%) had severe preeclampsia. Three of these had preeclampsia requiring delivery prior to 34 weeks, 9 had severe preeclampsia after 34 weeks’ gestation, and 2 patients of the latter group had eclampsia. Two patients with preeclampsia (8.3%) had a small-for-gestational-age (SGA) newborn defined as birthweight under the 10th percentile and 14 patients (6.0%) had an SGA newborn without preeclampsia.
The demographic characteristics and pregnancy-related data of the group with preeclampsia and the unaffected group are compared in the Table . Patients who developed preeclampsia had a significantly higher rate of risk factors by history and a higher BMI in the first trimester. There was a larger proportion of African American and Hispanic patients in the preeclampsia group (96%) as compared with the control group (82%), but the difference was not statistically significant. As expected, gestational age at delivery and mean birthweight were significantly lower in the preeclampsia group.
| Characteristic | Unaffected (n = 234) | Preeclampsia (n = 24) | P value |
|---|---|---|---|
| Maternal age, y, mean (range) a | 28.0 (18–45) | 26.3 (18–38) | NS |
| Ethnicity, n (%) b | NS | ||
| Caucasian | 26 (11) | 1 (4) | |
| African American | 77 (33) | 10 (42) | |
| Hispanic | 115 (49) | 13 (54) | |
| Asian/South Asian | 14 (6) | 0 (0) | |
| Other | 2 (1) | 0 (0) | |
| African American plus Hispanic | 192 (82) | 23 (96) | |
| Risk factors for preeclampsia by history, n (%) b , c | |||
| Prior history of preeclampsia | 13 (6) | 5 (21) | < .05 |
| Chronic hypertension | 9 (4) | 6 (25) | < .05 |
| Diabetes mellitus | 1 (0.4) | 2 (8) | < .05 |
| Sickle cell disease | 1 (0.4) | 0 (0) | NS |
| Chronic renal disease | 0 (0) | 1 (4) | NS |
| Systemic lupus erythematosus | 1 (0.4) | 0 (0) | NS |
| Nulliparity, n (%) b | 78 (33) | 15 (62.5) | < .05 |
| Mean BMI, kg/m 2 a | 27.0 (15-45) | 31.0 (10-49) | < .05 |
| BMI >30, b kg/m 2 | 51 (23%) | 10 (42%) | < .05 |
| CRL at first screen, mm d | 63.4 (43.7-84) | 63.0 (50.5-79.7) | NS |
| Placental location (posterior) b | 121 (52%) | 17 (71%) | NS |
| Mean gestational age at delivery, wks a | 39.1 (28.3-41.4) | 37.3 (30.4-40.9) | < .05 |
| Mean birthweight, g (range) a | 3300 (794–4625) | 2813 (954–4600) | < .05 |
| Birthweight centile, n (range) a | 43.2 (1–100) | 32.8 (5–94) | < .05 |
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